The prevalence of asthma has been steadily increasing for the past two decades, with an estimated 17 million cases in the United States alone. Once believed to be primarily a dysfunction in the contractile mechanisms of airway smooth muscles, recent studies have indicated the role of the immune system and inflammation in asthma and other pulmonary diseases.
Asthma is now characterized as a complex inflammatory disease attributed to the inappropriate stimulation of the immune system. In some cases, the inflammation is triggered by airborne antigens. In others, exogenous triggers cannot be defined (intrinsic asthma). The immune cells and mediators implicated in asthmatic inflammation include IgE, mast cells, eosinophils, T cells, interleukin-4 (IL-4), IL-5, IL-9, IL-13 and other cytokines (Bradding et al., 1994, Am. J. Respir. Cell Mol. Biol. 10:471-480; Bradding et al., 1997, Airway Wall Remodeling in Asthma, CRC Press, Boca Raton, Fla.; Nicolaides et al., 1997, Proc. Natl. Acad. Sci. USA 94:13175-13180; Wills-Karp, 1998, Science 282:2258-2260; Hamid et al., 1991, J. Clin. Invest. 87:1541-1546; Kotsimbos et al., 1996, Proc. Assoc. Am. Physicians 108:368-373). Of these immune cells and mediators, the role of T-helper type 2 (Th2) cells and cytokines is proving to be increasingly important, as they are believed to be responsible for initiation and maintenance of airway inflammation, as well as vital to B cell regulation, eosinophil function, mucus responses, and stimulation of airway remodeling (Elias et al., 1999, J. Clin. Invest. 104:1001-1006; Ray et al., 1999, J. Clin Invest. 104:985-993).
Immune-mediated inflammation is thought to lead to airway remodeling, or structural modifications, in the asthmatic airway. The end result of remodeling is believed to contribute to both the symptoms and physiological dysregulation of asthma. Remodeling is often characterized by airway thickening, mucus metaplasia, epithelial hypertrophy and airway fibrosis. Extensive fibrosis is widely considered to increase disease severity, airway hyperresponsiveness (AHR) and contribute to the generation of incompletely reversible airway obstruction (Elias et al., 1999, J. Clin. Invest. 104:1001-1006). Therefore, the successful design of therapeutics for the treatment of asthma requires an understanding of both the mechanisms of inflammation and the processes of injury and wound healing in the respiratory system.
Two prominent cytokines, IL-4 and IL-13, are believed to play an important role in the inflammation and airway remodeling of asthma and other pulmonary diseases. IL-4 and IL-13 are similar in that they are both produced by the same subset of Th2 helper T cells, have overlapping effector profiles, and share a receptor component and signaling pathways. However, the critical role of IL-13 over IL-4 in AHR, eosinophil recruitment, mucus overproduction, and other symptoms of asthma has been conclusively demonstrated (Wills-Karp, 1998, Science 282:2258-2260, Grunig et al. 1998, Science 282:2261-2263). Overexpression of IL-13 in the murine lung results in eosinophil, lymphocyte, and macrophage rich inflammation, mucus metaplasia, airway fibrosis, and AHR after methacholine challenge (Zheng et al., 1999 J. Clin. Invest. 103:779-788). Further, polymorphisms in both the IL-13 promoter and the coding region have been associated with the asthmatic phenotype (Heinzmann et al., 2000, Hum. Mol. Genet. 9:549-559). These results suggest that abnormal IL-13 production is a critical component of asthmatic inflammation and airway remodeling.
The role of IL-13 in inflammatory pulmonary diseases is not limited to asthma. Chronic obstructive pulmonary disease (COPD, clinically defined as chronic bronchitis, emphysema, and chronic obstructive lung disease) has long been thought of as a distinct disease from asthma. However, the similarities between the two diseases have been noted and have resulted in the formulation of the “Dutch Hypothesis”, that was first proposed in 1961. The most recent revision of the Dutch Hypothesis proposes that asthma and COPD, in some individuals, are not distinct processes, and that common pathogenic mechanism underlie these disorders. The hypothesis further states that a genetic predisposition to develop atopy, asthma, AHR and/or increased levels of IgE predispose cigarette smokers to develop COPD (Vestbo and Prescott, 1997, Lancet 350:1431-1434). Further, overexpression of IL-13 in the murine lung causes emphysema and COPD-like mucus metaplasia, IL-13 is overexpressed in biopsy and autopsy lung tissue from patients with COPD, and polymorphisms of IL-13 have been described that correlate with the presence of COPD. When these results are viewed in light of the Dutch Hypothesis, not only are asthma and COPD more closely related than previously thought, but the central role of IL-13 dysregulation in these pulmonary inflammatory disorders becomes more prominent.
The progress in illuminating the underlying mechanisms and causes of asthma, COPD and related pulmonary inflammatory disorders is striking considering the fact that what was once thought of as a malfunction of bronchial muscle contraction can now be linked to specific cytokines and cell types. Despite this progress, asthma remains, along with tuberculosis and AIDS, the only chronic disease with an increasing death rate. In addition, by 2020, COPD is expected to be the fourth leading cause of death in the world.
To counter the increasing morbidity and mortality due to asthma, the arsenal of medications for the treatment of asthma is ever increasing.
Asthma medications fall into two general categories, controllers and relievers. Controllers are for the prevention of asthma attacks before symptoms arise, and relievers are taken during the midst of an asthma attack. Controllers include corticosteroids, widely considered the most potent and effective anti-inflammatory drugs available, cromolyn sodium and nedocromil, milder anti-inflammatories often used in children, and long-acting beta-2 agonists, which are bronchodilators. Relievers include short acting beta-2 agonists and anticholinergenics, which are often used a supplements or alternatives to beta-2 agonists.
While corticosteroids and other therapeutics target the inflammatory-mediated symptoms of asthma, they often have broad-ranging immunosuppressive properties, as well as other deleterious side effects. As the physiological and biological mechanisms of asthma are elucidated, development of specific and effective drugs should closely follow, and the symptoms, morbidity, and mortality of asthma should drop, instead of its current rise. However, despite increased understanding of the underlying disease mechanism and despite the increasing incidence of asthma, and morbidity and death therefrom, there are currently a limited number of effective and safe treatments for asthma, COPD and other inflammatory diseases. In addition, there are no pharmacologic drugs that alter the progression of COPD.
Thus, there is a long felt and acute need for specific, effective treatments for asthma, COPD, and other inflammatory diseases. The present invention meets this need.